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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6815
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pubmed:dateCreated |
2001-1-3
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pubmed:databankReference |
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pubmed:abstractText |
Apoptosis is an essential process in the development and homeostasis of all metazoans. The inhibitor-of-apoptosis (IAP) proteins suppress cell death by inhibiting the activity of caspases; this inhibition is performed by the zinc-binding BIR domains of the IAP proteins. The mitochondrial protein Smac/DIABLO promotes apoptosis by eliminating the inhibitory effect of IAPs through physical interactions. Amino-terminal sequences in Smac/DIABLO are required for this function, as mutation of the very first amino acid leads to loss of interaction with IAPs and concomitant loss of Smac/DIABLO function. Here we report the high-resolution crystal structure of Smac/DIABLO complexed with the third BIR domain (BIR3) of XIAP. Our results show that the N-terminal four residues (Ala-Val-Pro-Ile) in Smac/DIABLO recognize a surface groove on BIR3, with the first residue Ala binding a hydrophobic pocket and making five hydrogen bonds to neighbouring residues on BIR3. These observations provide a structural explanation for the roles of the Smac N terminus as well as the conserved N-terminal sequences in the Drosophila proteins Hid/Grim/Reaper. In conjunction with other observations, our results reveal how Smac may relieve IAP inhibition of caspase-9 activity. In addition to explaining a number of biological observations, our structural analysis identifies potential targets for drug screening.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CASP9 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 9,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Cysteine Proteinase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/DIABLO protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Drosophila Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Insect Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Mitochondrial Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Neuropeptides,
http://linkedlifedata.com/resource/pubmed/chemical/Peptides,
http://linkedlifedata.com/resource/pubmed/chemical/Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/X-Linked Inhibitor of Apoptosis...,
http://linkedlifedata.com/resource/pubmed/chemical/grim protein, Drosophila,
http://linkedlifedata.com/resource/pubmed/chemical/reaper protein, Drosophila
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pubmed:status |
MEDLINE
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pubmed:issn |
0028-0836
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
408
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1008-12
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:11140638-Animals,
pubmed-meshheading:11140638-Binding Sites,
pubmed-meshheading:11140638-Carrier Proteins,
pubmed-meshheading:11140638-Caspase 9,
pubmed-meshheading:11140638-Caspases,
pubmed-meshheading:11140638-Crystallography, X-Ray,
pubmed-meshheading:11140638-Cysteine Proteinase Inhibitors,
pubmed-meshheading:11140638-Drosophila,
pubmed-meshheading:11140638-Drosophila Proteins,
pubmed-meshheading:11140638-Escherichia coli,
pubmed-meshheading:11140638-Hydrogen Bonding,
pubmed-meshheading:11140638-Insect Proteins,
pubmed-meshheading:11140638-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:11140638-Mitochondrial Proteins,
pubmed-meshheading:11140638-Models, Molecular,
pubmed-meshheading:11140638-Mutagenesis, Site-Directed,
pubmed-meshheading:11140638-Neuropeptides,
pubmed-meshheading:11140638-Peptides,
pubmed-meshheading:11140638-Protein Conformation,
pubmed-meshheading:11140638-Protein Structure, Tertiary,
pubmed-meshheading:11140638-Proteins,
pubmed-meshheading:11140638-Recombinant Fusion Proteins,
pubmed-meshheading:11140638-Structure-Activity Relationship,
pubmed-meshheading:11140638-X-Linked Inhibitor of Apoptosis Protein
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pubmed:articleTitle |
Structural basis of IAP recognition by Smac/DIABLO.
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pubmed:affiliation |
Department of Molecular Biology, Princeton University, New Jersey 08544, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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